Generally, a fistula is an abnormal connection or passageway between organs or vessels that normally do not connect. Fistulae can develop in various parts of the body. For example, types of fistulae, named for the areas of the body in which they occur, include anorectal fistula or fistula-in-ano or fecal fistula (between the rectum or other anorectal area and the skin surface), arteriovenous fistula or A-V fistula (between an artery and vein), biliary fistula (between the bile ducts to the skin surface, often caused by gallbladder surgery), cervical fistula (abnormal opening in the cervix), craniosinus fistula (between the intracranial space and a paranasal sinus), enteroenteral fistula (between two parts of the intestine), enterocutaneous fistula (between the intestine and the skin surface, namely from the duodenum or the jejunum or the ileum), enterovaginal fistula (between the intestine and the vagina), gastric fistula (between the stomach to the skin surface), metroperitoneal fistula (between the uterus and peritoneal cavity), perilymph fistula (a tear between the membranes between the middle and inner ears), pulmonary arteriovenous fistula (between an artery and vein of the lungs, resulting in shunting of blood), rectovaginal fistula (between the rectum and the vagina), umbilical fistula (between the umbilicus and gut), tracheoesophageal fistula (between the breathing and the feeding tubes) and vesicovaginal fistula (between the bladder and the vagina). Causes of fistulae include trauma, complications from medical treatment and disease.
Treatment for fistulae varies depending on the cause and extent of the fistula, but generally involves surgical intervention. Various surgical procedures are commonly used, most commonly fistulotomy, placement of a seton (a cord that is passed through the path of the fistula to keep it open for draining), or an endorectal flap procedure (where healthy tissue is pulled over the internal side of the fistula to keep feces or other material from reinfecting the channel). Surgery for anorectal fistulae is not without side effects, including recurrence, reinfection, and incontinence.
Inflammatory bowel diseases, such as Crohn's disease and ulcerative colitis, are the leading causes of anorectal, enteroenteral, and enterocutaneous fistulae. The reported incidence of fistula in Crohn's disease ranges from 17% to 50%. Management of fistulae in patients with Crohn's disease continues to present an extremely challenging problem since many such fistulae do not respond to available treatments. Such fistulae and their recurrence are a very distressing complication that significantly reduces the quality of life of affected patients. Recent improvements in medical treatment (e.g., treatment with Infliximab®) and expert surgical management have decreased the need for complicated surgery. However, many patients are not cured. Failure of fistulae to heal is probably due to the suboptimal quality of tissues that have been affected by Crohn's disease. Indeed, Crohn's fistulae provide a model system for wound healing under some of the worst possible conditions.
Perianal fistulas are a common complication of Crohn's disease,A1 which are estimated to affect up to 28% of patients in the first two decades after diagnosis,A2,A3 particularly those with colonic disease and rectal involvement.A4 They severely impair patients' quality of life and cause considerable morbidity.A5,A6 Approximately 70-80% of perianal fistulas are complex,A3,A7 and these are challenging to treat since they are particularly refractory to conventional treatment strategies (antibiotics, immunosuppressants) and anti-tumor necrosis factor (anti-TNF) therapies.A8-A12 Furthermore, 60-70% of patients relapse on stopping treatment,A13-A17 and only a minority of patients achieve long-term remission.A18 
Failure of or intolerability to medical therapy can ultimately result in debilitating surgical approaches, such as diverting stoma or proctectomy.A19 Therefore, there remains a huge unmet need for alternative medical treatments.
Mesenchymal stromal cells (MSCs) are non-hematopoietic stromal cells that are able to differentiate into mesenchymal tissues such as bone, cartilage, muscle, ligament, tendon, and adipose. MSCs can be easily isolated from tissues such as bone marrow or adipose tissue and rapidly expanded in culture. WO-A-2006/136244 describes the treatment of fistulae using adipose tissue-derived stromal stem cell-containing compositions. Adipose-derived mesenchymal stromal cells are a promising new therapeutic approach, which may be useful for the treatment of complex perianal fistulas due to their anti-inflammatory and tissue-regenerating potential.A20-A22 Initial proof of concept was previously obtained in an open-label phase ½a clinical study of allogeneic, expanded adipose-derived stem cells (eASC, Cx601) in 24 Crohn's disease patients with complex perianal fistulas with 56.3% of patients showing complete closure of the external opening and the absence of collections measured by MRI of the treated fistula 24 weeks after treatment.A23 
Complex perianal fistulas in Crohn's disease are particularly challenging to treat and there remains a need for establishing clinically proven therapies for the treatment of complex perianal fistulas in Crohn's Disease.